tbuckley/cabot-search huggingface dataset:
RADT-42. EFFECTS OF RADIOTHERAPY FOR CNS NEOPLASMS IN PEOPLE WITH MULTIPLE SCLEROSIS
Authors: Angela Phan, Yolanda Tseng, Jerome Graber
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Patients with multiple sclerosis (MS) may be at higher risk of brain tumors (Khalil 2012, London 2020, etc.). However, MS patients have been reported to have adverse effects from radiotherapy, a mainstay of CNS treatment. In the last ten years, radiation techniques have improved. We submit a case report of an MS patient with demyelinating CNS lesions shortly after radiation therapy for an astrocytoma and review the literature. Case description: A 40-year-old woman with a history of MS treated with Siponimod underwent resection of a right frontotemporal grade 2 astrocytoma, IDH mutant. She received adjuvant proton radiotherapy (54 Gy(RBE) over 30 fractions) followed by temozolomide chemotherapy. She tolerated radiotherapy well and only experienced grade 1 dermatitis, fatigue, and hair loss within the field of treatment. 1-month post radiation MRI was stable. 4 months post radiation there was an asymptomatic new typical demyelinating lesion on FLAIR without T1 or contrast changes. This was outside the high dose radiation field (i.e. received ~30 Gy(RBE)). Her Siponimod had been held for concerns of interactions with radiation or chemotherapy. DISCUSSION Cases have been reported of people with MS experiencing adverse effects from radiotherapy. Murphy, et al., reported a 30-year-old woman with MS experiencing an attack of demyelination 2 months after radiotherapy (50 Gy over 25 fractions), and Borges, et al. presents a 28-year-old patient who experienced radiotherapy-induced inflammatory demyelination after receiving whole-ventricular irradiation (24 Gy over 15 fractions). Miller, et al., reported 6 patients without exacerbations of MS but had developed grade 4 neurotoxicity in a median of 1 year; most of those patients were treated with older radiation techniques, however. Radiotherapy effects in people with MS is a topic that should be revisited in the era of more conformal RT techniques, effective MS therapies, and cancer treatment including immunotherapy.
EXTH-21. DEVELOPMENT OF THERAPEUTIC STRATEGIES BY PATHWAY-BASED MULTI-OMICS APPROACH AND MASTER KINASE ANALYSIS IN GLIOBLASTOMA MULTIFORME
Authors: Michael Oh, Mohammad Hasanain, Simona Migliozzi, Luciano Garofano, Fulvio D'Angelo, Anna Luisa Di Stefano, Julie Lerond, Jann Sarkaria, Michele Ceccarelli, Marc Sanson, Anna Lasorella, Antonio Iavarone
Journal: Neuro-Oncology (2022)

Abstract Current transcriptomic classification of Glioblastoma Multiforme (GBM) has been ineffective to predict survival and therapeutic vulnerabilities. Recently, we proposed a four-group functional classification of GBM that included proliferative/progenitor, neuronal, mitochondrial and glycolytic/plurimetabolic subtypes with prognostic and therapeutic implications as the mitochondrial subtype carries the best survival and exhibits distinct sensitivity to mitochondrial OXPHOS inhibitors. To uncover novel therapeutic targets for each functional GBM subtype, we focused on protein kinases for their attractive features as both drivers and drug targets, with current availability of 62 FDA-approved inhibitors available for cancer precision therapeutics. We designed an unbiased integrative, machine learning-based proteomics/phosphoproteomics network for the identification of Master Kinases (MKs) responsible for effecting key phenotypic hallmarks of each of the four GBM subtypes. Here we report the identification and validation of protein kinase C delta (PRKCd) and DNA-PKcs as MKs that sustain the glycolytic/plurimetabolic and proliferative/progenitor GBM subtypes, respectively. Genetic and pharmacologic inactivation of PKCd in GBM patient-derived organoids of the glycolytic/plurimetabolic subtype blocked glucose uptake and lipid accumulation, resulting in marked anti-tumor effects. We also validated the role of PKCd in oncometabolic processes at the intersection between insulin, IGF, and lipid metabolism. DNA-PKcs was qualified as MK for the proliferative/progenitor GBM subtype, which is characterized by high basal level of replication stress. Biochemical experiments showed activation of DNA-PK in GBM patient-derived organoids of the proliferative/progenitor subgroup. Targeting DNA-PK in proliferative/progenitor GBM organoids with the clinically tested DNA-PKcs inhibitor nedisertib in association with gamma irradiation, the essential component of the standard of care for patients with GBM, led to an unsustainable level of DNA damage and massive GBM cell death selectively in this GBM subtype. As DNA-PKcs inhibitors have been introduced into clinical trials, our findings suggest that pre-selection of patient with PPR tumors is likely to enhance therapeutic success.
TMET-08. METABOLOMIC CHANGES IN GLIOBLASTOMA PATIENTS UNDERGOING CONCURRENT CHEMORADIATION THERAPY
Authors: Orwa Aboud, Yin Allison Liu, Oliver Fiehn, Christopher Bridges, Ruben Fragoso, Rawad Hodeify, Orin Bloch
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE To illustrate changes of untargeted metabolomics in patients with glioblastoma IDH wildtype undergoing concurrent radiation therapy (RT) with temozolomide (TMZ). This study implemented machine learning (ML) algorithms to predict treatment phase: pre-surgery, post-surgery, pre-radiation, and post radiation based on untargeted metabolomics data. METHODS Thirty-six patients with glioblastoma IDH wildtype (18 methylguanine methyltransferase [MGMT] methylated, 16 MGMT unmethylated, 2 MGMT status unknown) were enrolled into this study. Serum samples obtained from patients on the same day before surgery, 2 days after surgery, before starting their concurrent chemoradiation, and after concluding this phase of treatment. Blood samples were obtained via antecubital phlebotomy without regard for time of the day, diet, or fasting status. Untargeted metabolomics by GC-TOF mass spectrometry were obtained and compared. The proposed ML models analyzed 105 samples from 36 patients utilizing 157 structurally identified blood metabolites. Multinomial Logistic Regression (MLR) and GradientBoostingClassifier (GB Classifier) were used to classify patient samples based on detected changes in blood metabolites. The classification performance of these models was evaluated using performance metrics and AUC scores. RESULTS Post radiation; significant increase in the following metabolites: glycine, serine, threonine, oxoproline, 6-deoxyglucose, gluconic acid, glycerol-alpha-phosphate, ethanolamine, propyleneglycol, triethanolamine, xylitol, and fumaric acid were noted while significant decrease in 3-aminopiperidine 2,6-dione was noted post radiation. MLR produced 78% accuracy, 75% precision, and AUC = 0.89, and GB Classifier produced 75% accuracy, 77% precision and AUC = 0.91. Finally, we presented a pattern of metabolites changes per clinical stage based on pairwise correlations. CONCLUSIONS This study represent the first serum metabolic signature associated with RT in patients with glioblastoma. The results from the classification algorithms and pairwise correlations showed that blood metabolites have the potential to predict phase of treatment and potentially enable to evaluate response to treatment in patients with glioblastoma in a relatively small cohort.
QOL-24. SILVER LININGS: THE EXPERIENCE OF POSTTRAUMTIC GROWTH IN NEURO-ONCOLOGY CAREGIVERS
Authors: Kelcie Willis, Autumn Lanoye, Christopher Kleva, Morgan Reid, Amber Fox, Jaclyn Sadicario, Julia Brechbiel, Ashlee Loughan
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Posttraumatic Growth (PTG) refers to positive psychological changes resulting from a traumatic event. A brain cancer diagnosis may be experienced as traumatic—not only for patients, but also for their caregivers. While caregivers in neuro-oncology consistently report significant emotional distress throughout the disease trajectory, their experience of PTG is unknown. METHODS Cross-sectional data were obtained from patients (N = 101, Mage = 50 years, 59% female, 86% White, 47% high-grade) diagnosed with primary brain tumors and their caregivers (N = 62, Mage = 50 years, 79% female, 92% White, 58% spouses) during routine clinic visits or online following the precautions of COVID-19. Patients and caregivers completed the Post Traumatic Growth Inventory, where &amp;gt; 46 and &amp;gt; 3 represent the clinical cutoffs for high versus low PTG. We compared caregiver and patient PTG using descriptive statistics and independent samples t-test. RESULTS Caregivers’ total PTG score was in the low range (M = 44.58, SD = 20.95) and significantly lower than patients’ total PTG (M = 51.78, SD = 21.96, p = .04). All five of caregivers’ subscale scores were also considered to be in the low range. Nevertheless, 45% of caregivers demonstrated moderate-to-high total PTG (compared to 67% of patients), and 65% reported moderate-to-high PTG in at least one subscale (compared to 85% of patients). Similar to patients, caregivers reported the most growth in Appreciation for Life (M = 2.98, SD = 1.05) and the least growth in New Possibilities (M = 1.71, SD = 1.17). CONCLUSIONS Results mirror previous findings in neuro-oncology, where caregivers consistently demonstrate greater emotional distress than patients. The current study suggests caregivers may also experience fewer positive changes. Overall, caregivers would benefit from increased support to process traumatic experiences associated with the disease. Future research should continue to investigate predictors of PTG in this vulnerable sample.
RADT-03. GOLDILOCKS AND THE THREE DOSES OF RADIOSURGERY FOR SMALL BRAIN METASTASES
Authors: Tugce Kutuk, Rupesh Kotecha, Ranjini Tolakanahalli, Haley Appel, Matthew Hall, D Jay Wieczorek, Yongsook Lee, Michael McDermott, Manmeet Ahluwalia, Alonso Gutierrez, Minesh Mehta, Martin Tom
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION The optimal dose for single-fraction radiosurgery (SRS) for small brain metastases (BM) (&amp;lt; 2 cm) has not been established considerable variability in dose selection. METHODS Consecutive patients diagnosed with intact BM &amp;lt; 2 cm in maximum dimension treated with SRS to prescription doses of 24, 22, or 20 Gy on the Gamma Knife® between 3/2019-1/2021 were reviewed. Institutional dosing prescriptions were: 24 Gy for &amp;lt; 10 lesions, 22 Gy for 10-20, and 20 Gy for &amp;gt;20). Endpoints included freedom-from-local-failure (FFLF) and radionecrosis on a per-lesion basis calculated from date of SRS to event. Univariable and multivariable analyses were performed using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS 133 patients with 863 BM met inclusion criteria. Prescription dose was 24 Gy for 416 (48.2%) lesions, 22 Gy for 266 (30.8%), and 20 Gy for 181 (21.0%). 20 Gy was associated (all p&amp;lt; 0.001) with younger age, presence of extracranial-disease, progressive extracranial-disease, lung primary, higher number of BM per SRS course (median 17 for 20 Gy, 14 for 22 Gy, 6 for 24 Gy), and smaller per-lesion tumor volume. With a median follow-up of 15 months, 76 (8.8%) LFs occurred. Actuarial 1-year FFLF was 91.2% (95%CI: 88.6-94.8%) for 24 Gy, 92.5% (89.1-95.9%) for 22 Gy, and 77.9% (71.2-84.6%) for 20 Gy (p&amp;lt; 0.001). On multivariable analysis, factors independently associated with adverse FFLF (all p&amp;lt; 0.05) were male sex, presence of extracranial-disease, breast or lung primary, and 20 Gy prescription dose (HR: 2.52, 95%CI: 1.34-4.76). The cumulative 1-year radionecrosis rate was 7.0% for 24 Gy, 4.0% for 22 Gy, and 3.8% for 20 Gy (p=0.035). CONCLUSION For BM &amp;lt; 2 cm, we propose a testable hypothesis that 22 Gy prescription dose may represent the “Goldilocks zone”- superior to 20 Gy regarding LF and superior to 24 Gy concerning radionecrosis.
RADT-38. INCIDENCE OF HEARING IMPAIRMENT AFTER DEFINITIVE PROTON BEAM THERAPY FOR MALIGNANCIES OF THE BRAIN AND BASE OF SKULL
Authors: Simona Gaito, Eunji Hwang, Marianne Aznar, Verity Ahern, David Twaithes, Anna France, Peter Sitch, Daniel J Indelicato, Adam Holtzman, Shermaine Pan, Ed Smith, Gillian Whitfield
Journal: Neuro-Oncology (2022)

Abstract AIM Aim of the project is to report the incidence of moderate/severe (G ≥ 3) long-term hearing impairment (HI) and to identify risk factors in patients treated for malignancies of the brain and base of skull with definitive Proton Beam Therapy (PBT) within the Proton Overseas Programme (POP). METHODS Clinical and treatment-related data from patients’ files stored in a national database and curated by a dedicated outcomes unit were extracted and analysed. Clinical toxicity data from the POP were graded as per Common Terminology Criteria for Adverse Events (CTCAE 4.0). Dosimetric data (Dmean to the cochlear structures) were extracted from the Treatment Planning System Proknow. For the purpose of this analysis, patients with radical definitive PBT only were selected. RESULTS Between 2008 - 2018, 229 UK patients received radical PBT overseas for Craniopharyngioma (104 patients;45.4%), Chordoma (60; 26.2%), Chondrosarcoma (53;23.1%), Meningioma (7;3%), Pituitary Adenoma (5;2.1%). Median age was 17 years (1-77). Median prescription dose was 55.8 Gy (45-75.8). Median dose to the Left and Right cochleas were 14.18 Gy (0-85.15) and 12.55 Gy (0-77.50), respectively. Eight patients developed G ≥ 3 HI (3.5%). Of those, 7 had received dose escalated treatments for radioresistant tumours (chordomas or condrosarcomas). In 4/8, the HI was bilateral. The median cochlear dose for the structures who developed G ≥ 3 HI was 48.99 Gy (10-76.87). CONCLUSIONS Incidence of G ≥ 3 HI in this patient population compares with historical cohorts, and, as expected, is higher in patients who receive dose escalated treatments for radioresistant tumours of the base of skull. Median dose in those who developed HI supports the use of dose constraints used in the clinical PBT practice.
CNSC-37. ATYPICAL GERMLINE MUTATIONS AND PRIMARY CNS TUMORS: A SINGLE-CENTER CASE SERIES AND LITERATURE REVIEW
Authors: Trusha Shah, Amber Ruiz, Che Ross, Marianne Dubard-Gault, Jerome Graber
Journal: Neuro-Oncology (2022)

Abstract A growing spectrum of germline mutations and their association with primary CNS tumors has been described over the last decade. These germline mutations are implicated in regulation of DNA integrity and repair, telomere maintenance, and cell cycle regulation resulting in aberrant cellular proliferation and immune surveillance evasion. To date, there are no well-defined guidelines for primary CNS tumor surveillance for these patients. Moreover, the exact role of traditional chemotherapy, immunotherapy, and radiation is unclear. We present a single-institution case series of adult patients with primary CNS tumors with atypical germline mutations and literature review. The most common germline mutations encountered involved heterozygous mutations of one of the mismatch repair (MMR) genes (MSH2, PMS2, MLH1). All patients developed high-grade gliomas defined as astrocytoma or glioblastoma WHO grade 4 based on the WHO 2021 classification. Germline mutations involving RAD51C, POT1, IDH1/2, MutyH, NTHL1, PALB2, and CHEK2 were associated with gliomas of variable grades and molecular subtypes. Non-glial tumors, including atypical rhabdoid tumors, medulloblastomas, hemangioblastomas, and meningiomas were found in association with germline SMARCB1, ATM, BRCA1, and CHEK2 mutations respectively. Review of the existing literature and knowledge obtained from our case series suggests several important concepts: (1) there is an increased risk of both glioma and non-glial tumor types in several atypical germline mutations, (2) multiple risk genes or variants of unknown significance likely contribute to primary brain tumor formation, (3) germline MMR mutations associated with high-grade glioma may be MMR gene-specific with potential increased risk of resistance and/or disease progression in the presence of alkylating agents such as temozolomide, (4) several germline mutations may increase risk of secondary tumor development after radiation, and (5) the role of screening for atypical germline mutations and subsequent disease surveillance remain unanswered.
DISP-07. SURVIVAL ANALYSIS OF GLIOBLASTOMA PATIENTS IN PENNSYLVANIA ACCORDING TO AREA DEPRIVATION INDEX AND IDH STATUS
Authors: Angel Baroz, Caleb Stahl, Debarati Bhanja, Hannah Wilding, Alireza Mansouri
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Glioblastoma (GBM) is the most aggressive primary brain tumor with a universally poor prognosis. Living in disadvantaged neighborhoods is associated with poor health outcomes, including increased cancer incidence. This study was designed to elucidate the relationship between GBM patients’ survival, isocitrate dehydrogenase (IDH) mutation status, and residential areas of deprivation in the state of Pennsylvania. METHODS Patients from Pennsylvania with a pathological diagnosis of GBM WHO Grade IV between January 2007 and December 2018 were retrospectively reviewed in the Penn State Health database. Demographic variables and molecular features were assessed. Area Deprivation Index (ADI) is a validated measure of regional socioeconomic deprivation that indexes neighborhoods by percentile, with low ADI scores representing less deprivation. Patients were assigned to low ( &amp;lt; 50) or high ( ≥ 51) ADI groups. Survival was measured against IDH status and ADI score; log-rank tests were performed. RESULTS 121 GBM WHO Grade IV patients were identified (median age at diagnosis: 63, 39.7% female, 60.3% male, 93.4% of white race). Among those, 64 (52.9%) had low ADI, and 57 (47.1%) had high ADI. Patients with high ADI had similar overall survival (OS) rates and progression free survival (PFS) at 18 months (56% OS, 95% confidence interval [CI]: 48-64%; 37.4% PFS, 95%CI: 30-44%; P=0.27) compared to patients with low ADI (50% OS, 95%CI: 43-57%; 32.4% PFS, 95%CI: 26-39%; P = 0.27). Further classification by IDH status resulted in 17 (14%) IDH mutant (IDHm) and 104 (86%) IDH wildtype (IDHwt) patients. Survival analysis demonstrated no significant difference in OS between IDHwt and IDHm patients, regardless of ADI score. CONCLUSION The aggressive nature of GBM requires early diagnostic approaches to impact survival. Living in socioeconomic disadvantaged areas may diminish survival outcomes; however, our data indicate that GBM may be too aggressive for ADI to have a significant impact on prognosis.
SURG-15. MINIMALLY INVASIVE PREFRONTAL APPROACH FOR GLIOMAS: TECHNICAL DESCRIPTION AND ASSOCIATED COMPLICATIONS
Authors: Francisco Marcó del Pont, Martin Merenzon, Alexis Morell, Dominique Higgins, Nitesh Patel, Michael Kader, Daniel Eichberg, Ashish Shah, Michael Silva, Evan Luther, Victor Lu, Ricardo Komotar, Michael Ivan
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Classical prefrontal approaches exposed the lateral surface of the frontal lobe. Minimally invasive (MI) approaches achieved to reduce soft tissue damage and craniotomy size without affecting tumor resection grade. This is associated with shorter hospital stays and faster return to preoperative daily activities. OBJECTIVE To describe the MI prefrontal glioma resection technique developed in our department and to analyze our surgical results. METHODS We performed a retrospective review of patients who underwent prefrontal lobe glioma (WHO grade II-IV) resection using an MI approach in 2016-2021 at the University of Miami Hospital. Re-surgery, biopsy-only patients, multicentric tumors, and patients with less than four months of follow-up were excluded. Demographic and clinical data were collected. A 4-5 cm linear incision is done, starting at 1 cm lateral to the sagittal suture and extending towards the superior temporal line. An ellipsoidal-shaped mini-craniotomy is performed. RESULTS Thirty-four patients were included. The mean age was 50.2 years old, with 20 male subjects. Twenty-two patients had high-grade gliomas (HGG) and 12 patients had low-grade gliomas (LGG). On average, patients were discharged 1.97 days after surgery. The mean craniotomy area was 15,5 cm2 (7-43 cm2). The mean tumor volume was 64,5 cm2 ( 9 -165.8 cm2). Two wound infections and one case of aseptic meningitis were observed in patients with craniotomies &amp;gt; 15 cm2, while the group with craniotomies &amp;lt; 15 cm2 had no perioperative complications. In the HGG group, a supramaximal resection (SMR) was achieved in 8 patients, 9 HGG patients had gross total resection (GTR) or near-total resection (NTR), and 5 patients had subtotal resection (STR). In the LGG, GTR was achieved in 10 patients and STR in 2 patients. CONCLUSION MI prefrontal approach for frontal gliomas is safe and feasible with minor complications, short hospital stay, and without sacrificing tumor resection volume.
CSIG-15. DEFINING THE ROLE OF HISTONE H3 K27 METHYLATION AND H3.3 S31 PHOSPHORYLATION IN H3.3K27M MUTANT DIFFUSE MIDLINE GLIOMAS
Authors: Faruck Hakkim, Charles Day, Florina Grigore, Alyssa Langfald, Igor Entin, Edward Hincliffe, James Robinson
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline gliomas (DMG) are aggressive high-grade gliomas that characteristically occurs in children. Heterozygous K27M mutation occurs in histone H3.3 as early events in DMG and are sufficient to drive a global reduction of H3K27 methylation (H3K27me) on all histone H3 variants. Histone H3K27me is responsible for epigenetic gene repression, and loss of K27me is associated with epigenetic dysregulation. However, histone H3.3 has a unique Chk1 phosphorylation site, Serine 31, critical for mitotic checkpoint regulation. Masking of S31 phosphorylation results in the abrogation of cell cycle checkpoints that monitor the alignment and segregation of chromosomes. DMG cells have decreased levels of mitotic S31P and are chromosomally unstable and aneuploid. Genomic-editing of H3.3 to revert the K27M mutation restores mitotic S31P and K27me and significantly reduces the rate of chromosome instability (CIN). Expression of H3.3 K27M or a non-phosphorylatable S31A mutant in normal, diploid cells results in chromosome missegregation and cell cycle checkpoint defects; and cells fail to undergo G1 cycle arrest leading to aneuploidy. H3.3 K27M and S31A inhibit p53 accumulation. In a mouse model of DMG, H3.3K27M and H3.3S31A promoted the development of high-grade gliomas, whereas H3.3WT controls did not. H3.3S31A is WT for K27me, demonstrating that loss of S31P is oncogenic. It remains unclear if it is the H3.3 K27M mutations or the associated loss of H3K27me3 that drives the reduction of S31P. The PRC2 complex is responsible for H3K27me, catalyzed by methyltransferases subunits EZH1 and EZH2. We used genome editing to knockout EZH1 and EZH2 in DMG cells and untransformed human diploid cell lines. Deletion of EZH2 causes a loss in K27 tri-methylation, and EZH1/2 knockouts causes a global loss of K27me. Ongoing studies examine how the loss of K27me affects gene expression, proliferation, H3.3S31P, chromosome missegregation, and aneuploid.